Chemokines are secreted proteins that are involved in the migration of leukocyte subsets to sites of inflammation, lymphopoiesis, angiogenesis and lymphoid organ development (Nelson and Krensky (2001) Immunity 14:377-86; Campbell et al. (2003) Immunol Rev 195:58-71; Moser et al. (2004) Trends Immunol 25:75-84; Moriguchi et al. (2005) J Biol Chem 280:17408-14). Chemokines, through their action in inducing cellular chemotactic responses, play a role in various inflammatory and infectious diseases. The two main subfamilies are distinguished by the position of the first two cysteines, either separated by one amino acid (CXC chemokines) or adjacent (CC chemokines) (Zlotnik and Yoshie (2000) Immunity 12:121-7; Loetscher and Clark-Lewis (2001) J Leukocyte Biol 69:881-4). Chemokines mediate their function by binding to seven transmembrane G protein-coupled receptors (Murphy et at (2000) Pharmacol Rev 52:145-76).
The chemokine Stromal cell-Derived Factor 1 (SDF-1/CXCL12) is the only known natural ligand for the receptor CXCR4. Recent reports suggest that SDF-1 may serve as a ligand for a second receptor, RDC1 (CXCR7) (Balabanian et al. (2005) J Biol Chem 280:35760-35766). CXCR4 is widely expressed on both hematopoetic and non-hempatopoetic cell and is found to be expressed on certain tumor cells. It has been suggested that SDF-1 plays a role in directing metastasis of CXCR4+ tumor cells to organs such as lymph node, lung, liver and bone that highly express SDF-1 (Kucia et at (2005) Stem Cells 23:879-894). Additional studies have shown that mesenchymal or marrow-derived stromal cells within the tumor microenvironment constitutively secrete SDF-1 (Burger and Kipps 2005).
Murine SDF-1 knockout models show that SDF-1 is critical for colonization of bone marrow by fetal liver derived hematopoietic stem cells during embryogenesis, retention of these cells in adult life, blood vessel formation in the gastrointestinal tract, cardiac ventricular septum formation and cerebellar differentiation (Nagasawa et al. (1996) Nature 382:635-8; Ma et al. (1999) Immunity 10:463-71; You et al. (1998) Nature 393:595-9). SDF-1 has also been suggested to be involved in activation of both Jak and Stat kinases (Vila-Coro et al. (1999) FASEB J13:1699-1710; Zhang et al. (2001) Blood 97:3342-8). Also, in diabetics with proliferative diabetic retinopathy, SDF-1 levels were shown to be increased locally in the eye (Butler et al. (2005) J Clin Invest 115:86-93).